Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Iriniotecan Treatment [T88.7]

OMIM number: 191740 (UGT1A1)

Dipl.-Biol. Birgit Busse

Scientific Background

The enzyme UDP-glucuronyltransferase 1A1 (UGT1A1) plays a major part in the enzymatic degradation of irinotecan, a topoisomerase I inhibitor. Through glucuronidation, the active metabolite SN38 is converted into the inactive metabolite SN38G and can thus be excreted hepatobiliary or renally. A dinucleotide expansion in the promoter region of the UGT1A1 gene reduces the synthesis of the enzyme to approximately 30% of the standard (cf. Gilbert's syndrome). As a result the detoxification process for SN38 is impaired. The accumulation of SN38 in the organism leads to severe side-effects, such as myelosuppression and poorly treatable diarrhoea, which further weakens the tumor patients. Determination of the UGT1A1 genotype prior to treatment provides the opportunity for individual adaption of dosage as well as prevention of undesired side-effects. The FDA has included the association of enzyme activity, genotype and dosage into the warnings/precautions section in the prescribing information.